Mechanistic Investigations of the Cyclocondensation Step of the Knorr Pyrrole Synthesis

A mechanistic investigation of the cyclocondensation step of the Knorr pyrrole synthesis of pyrrolo[2,1,5-cd]indolizidines is reported.Kinetic isotope effect measurements suggest the participation of two protic solvent molecules in a rate-determining ketone protonation prior to cyclization and dehydration.Although the pyrrole ring system is a prominent and widely-occurring motif within biologically-active natural products, pharmaceutical agents, and other useful synthetic materials (such as 1-3, Figure 1), 1,2 their preparation, particularly when fully substituted, can provide a high challenge for synthetic chemistry.As a result, many methods exist for the preparation of this heterocycle, 3 one of the earliest being the classic Knorr pyrrole synthesis first described in 1884.As shown in Scheme 1, this sequence involves a cyclocondensation reaction of appropriate acyclic starting materials. 4N MeO MeO O O MeO OSO 3 Na MeO HO 1: lamellarin !20-sulfate N NH HN N NH 3 Cl